An Integrated Analysis for Selecting Ibrutinib-Based Combination Therapy in CLL

The following article features coverage from the American Association for Cancer Research (AACR) 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

An investigation based on the integration of a measure of chromatin accessibility with ex vivo phenotypic drug responses in patients with chronic lymphocytic leukemia (CLL) showed promise for the evaluation of new combination treatments for this disease. The findings from this study were presented at the American Association for Cancer Research (AACR) Annual Meeting 2019.¹

Although many patients with CLL respond to treatment with ibrutinib, a Bruton’s tyrosine kinase inhibitor, limitations of this therapy include slow, and often incomplete, responses, and CLL cell redistribution to the periphery. Furthermore, patients receiving ibrutinib for CLL may eventually develop ibrutinib-resistant disease that is difficult to treat. These findings have prompted searches for effective ibrutinib-based combination therapies. 

In this study, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) was used to evaluate peripheral blood specimens from 24 patients with CLL collected before and after treatment with ibrutinib to map the chromatin regulatory landscape and assess for specific types of epigenetic deregulation that may drive the disease in individual patients. In addition, an ex vivo, single-cell, cytotoxicity profiling method called Pharmacoscopy^{2 (}involving automated confocal microscopy) was used to evaluate chemosensitivity to more than130 drugs on paired CLL samples.

Results obtained from these 2 assays were integrated and applied toward the prioritization of targets for combination therapy. Based on these results, samples from 8 ibrutinib-naive patients with CLL were treated with selected drugs administered with and without ibrutinib. Results showed increased sensitivity to proteasome, PLK1, and mTOR inhibitors during treatment with ibrutinib; these results were reported to be subsequently validated with other methods. 

Disclosure: The presenters disclosed financial ties to various pharmaceutical companies. For a full list of disclosures, please see the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of AACR 2019 meeting by visiting the conference page.

References

1. Vladimir GI, Schmidl C, Renderio A, et al. Integrated ATAC-seq and single-cell synergistic chemosensitivity profiling identifies rational drug combinations in ibrutinib treated CLL patients. Presented at: American Association for Cancer Research (AACR) Annual Meeting 2019; March 29–April 3, 2019; Atlanta, GA. Abstract 319/10. 
2. Snijder B, Vladimer GI, Krall N, et al. Image-based ex-vivo drug screening for patients with aggressive haematological malignancies: interim results from a single-arm, open-label, pilot study. Lancet Haematol. 2017;4(12):e595-e606.